5-benzoyloxy-2-lower alkyl decahydroisoquinolines

ABSTRACT

DISCLOSED ARE 5,6,7 OR 8-HYDROXY-2-ALKYL-1,2,3,4-TETRAHYDROISOQUINOLINES; 5,6,7 OR 8-HYDROXY-2-ALKYL DECAHYDROISOQUINOLINES AND ESTERS, ACID ADDITION SALTS AND QUATERNARY AMMONIUM SALTS THEREOF. THE COMPOUNDS HAVE BIOLOGICAL ACTIVITY IN ANIMALS. SOME INCREASE ARTERIAL BLOOD FLOW. OTHER INDUCE ANTIARRHYTHMIC ACTIVITY IN ANIMALS, ESPECIALLY 5(3,4,5-TRIMETHOXY-BENZOYLOXY)-2-METHYL OR ETHYL DECAHYDROISOQUINOLINE.

United States Patent ABSTRACT OF THE DISCLOSURE Disclosed are 5,6,7 or 8-hydroxy-2-alkyl-1,2,3,4-tetrahydroisoquinolines; 5,6,7 or 8-hydroxy-2-alkyl decahydroisoquinolines and esters, acid addition salts and quaternary ammonium salts thereof. The compounds have biological activity in animals. Some increase arterial blood flow. Others induce antiarrhythmic activity in animals, especially 5(3,4,5-trimethoxy-benzoyloxy)-2-methyl or ethyl decahydroisoquinoline.

This application is a continuation-in-part of my copending application Ser. No. 564,001, filed July 11, 1966, now US. Pat. No. 3,475,538 issued Oct. 28, 1969, which is in turn a continuation-in-part of copending application Ser No. 472,660, filed July 16, 1965, now US Pat. No. 3,379,730, issued Apr. 23, 1968.

This invention relates to novel chemical compounds and processes of preparing the same. More particularly, this invention is concerned with novel reduction products of hydroxyisoquinolines, particularly such products having biological activity, and novel chemical processes of preparing such reduction products.

According to one aspect of the present invention there are provided novel 5,6,7 or 8-hydroxy-2-R-1,2,3,4-tetrahydroisoquinolines of the formula wherein R is a lower alkyl, particularly those having 1 to 5 carbons such as methyl, ethyl and propyl, and esters and salts thereof, and novel 5,6,7 or 8-hydroxy-2-R-decahydroisoquinolines of the formula wherein R is hydrogen or a lower alkyl, particularly those having 1 to 5 carbons such as methyl, ethyl and propyl,

"ice

hydroxy-2-lower alkyl isoquinoline quaternary salt. This process can be represented as follows:

HO HO wherein R is lower alkyl and X is an anion such as the chloride or bromide ion.

The quaternary salts of the hydroxyisoquinolines can be produced conveniently by reaction of a 5,6,7 or 8- hydroxyisoquinoline with an alkyl halide. Alkyl halides such as methyl chloride, ethyl bromide and propyl bromide may be used in the reaction. The reaction is readily effected by combining the hydroxyisoquinoline and alkyl halide in a suitable liquid reaction medium such as a lower alcohol and particularly ethanol. The reaction mixture can be heated, such as at reflux, to promote the reaction. The desired product can then be recovered from the reaction mixture by conventional isolation techniques.

Reduction of the 5,6,7 or 8-hydroxy-2-lower alkyl isoquinolinium halide using moderate catalytic hydrogenation procedures gives the desired 5,6,7 or S-hydroxy-Z- lower alkyl-1,2,3,4-tetrahydroisoquinoline in the form of a hydrohalide salt which upon treatment with a base such as sodium hydroxide yields the free tertiary amine.

This reduction is conveniently eifected using hydrogen at a moderately elevated pressure, such as about 25 to p.s.i., a finely divided platinum oxide catalyst and room temperature. To facilitate the reduction the isoquinoline compound is first dispersed in a suitable organic liquid and advisably one in which the isoquinoline salt is soluble. Ethanol is a particularly suitable solvent for the halide salts. The progress of the reduction can be followed -by the hydrogen uptake. Once the theoretical amount of hydrogen has been consumed the reduction can be terminated, the mixture filtered and the filtrate concentrated to crystallizethe desired product as the hydrohalide salt.

Some of the 2-alkyl tetrahydroisoquinolines which may be produced as described are:

5-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline,

5-hydroxy-2-ethyl-1,2,3,4-tetrahydroisoquinoline,

5 -hydroxy-2-propyl-1,2,3,4-tetrahydroisoquinoline, 7-hydroxy-2-ethyl-l,2,3,4-tetrahydroisoquinoline, and 6-hydroxy-2-butyl-1,2,3,4-tetrahydroisoquinoline.

The tertiary hydroxyisoquinolines, as the free bases, are reduced to hydroxy decahydroisoquinolines by hydrogenation in glacial acetic acid using platinum oxide as the catalyst. The process can be represented as follows:

3 droxy decahydroisoquinoline and 7-hydroxy decahydroisoquinoline.

In order to produce the 5,6,7 or S-hydroxy-l-lower alkyl decahydroisoquinolines it appears necessary to first convert the 5,6,7 or 8-hydroxy-2-lower alkyl isoquinolinium halide to the corresponding hydroxide and to then hydrogenate the resulting hydroxide. Production of the hydroxide can be readily achieved by reacting the halide with silver oxide. This reaction can be illustrated as follows:

wherein R is a lower alkyl such as one having 1 to carbons including methyl, ethyl and propyl and X is a halide ion. The reaction proceeds readily in an aqueous lower alcohol such as 50% methanol. The desired product can be isolated from the reaction mixture by conventional procedures. Among the compounds which may be produced in this way are 5-hydroxy-2-ethylisoquinolinium hydroxide, S-hydroxy-2 methylisoquinolinium hydroxide, 7-hydrox 2-propylisoquinolinium hydroxide and 8-hydroxy-2-ethylisoquinolinium hydroxide.

Conversion of the 5,6,7 or 8-hydroxy-2-lower alkyl isoquinoliniurn hydroxide to the 5,6,7 or 8-hydroxy-2-lower alkyl decahydroisoquinoline can be effected by hydrogenation in glacial acetic acid using a platinum oxide catalyst. The process using the hydroxide starting material can be represented as follows:

HO HO wherein R is a lower alkyl such as one having 1 to 5 carbons including methyl, ethyl and propyl.

Some of the 5,6,7 or 8-hydroxy-2-lower alkyl decahydroisoquinolines which may be produced as described are S-hydroxy-Z-ethyl decahydroisoquinoline, 5-hydroxy-2- methyl decahydroisoquinoline, S-hydro-xy-Z-propyl decahydroisoquinoline, 6-hydroxy-2-butyl decahydroisoquinoline, 7-hydroxy-2-ethyl decahydroisoquinoline and 8-hyresented by the formulae R4 R3 R4 and +=O where R is lower alkyl and particularly a lower alkyl having 1 to 5 carbons such as methyl, ethyl and propyl and R R and R are hydrogen, a lower alkyl and particularly a lower alkyl having 1 to 5 carbons such as methyl and ethyl, a lower alkoxy and particularly a lower alkoxy having 1 to 5 carbons such as methoxy and ethoxy, or a halo group such as the chloro, bromo and fluoro groups.

The esters may be produced by reacting the appropriate benzoyl halide with a 5,6,7 or 8-hydroxy-2-lower alkyl-1, 2,3,4-tetrahydroisoquinoline or a 5,6,7 or S-hydroxy-Z- lower alkyl decahydroisoquinoline. These reactions can be represented as follows:

wherein X is a reactive halogen, particularly chlorine or bromine and R R R and R have the assigned significance.

Among the benzoyl halides which can be used as reactants are benzoyl chloride, 4-bromobenzoyl chloride, 2-methylbenzoyl chloride, 3-methoxybenzoylchloride and 3,4,5-trimethoxybenzoyl chloride.

5,6,7 or 8-hydroxy 2. lower alkyl-1,2,3,4,-tetrahydroisoquinolines or decahydroisoquinolines such as those named and described above can be used as reactants.

The esterification is readily effected in an organic solvent under anhydrous conditions at moderately elevated temperatures and advis'ably under reflux conditions. Dry benzene and toluene are particularly suitable reaction media. After the reaction is terminated the desired product can be isolated from the reaction mixture by conventional procedures. Somewhat higher esterification temperatures are used to esterify the decahydro compounds because the hydroxy group on such compounds is less reactive than on the aromatic nucleus present in the 1,2,3,4-tetrahydroisoquinolines.

Some of the esters which may be formed as described,

using the appropriate reactants are:

Acid addition salts of the bases of this invention are produced by contacting the compounds with an organic or inorganic acid such as hydrochloric, sulfuric, formic, citric, maleic, succinic and fumaric acids.

Quaternary ammonium salts are formed by contacting the compounds with a suitable alkylating agent such as dimethyl sulfate or an alkyl halide such as methyl chloride and ethyl bromide.

The compounds of this invention, being amines, have use as neutralizing agents. In addition, the compounds may be used in the isolation and purification of penicillin with which they will form salts.

The compounds of this invention also possess biological activity in animals and thus are potentially useful as drugs. They can be used as biologically active standards in evaluating other compounds for similar activity in animals.

A compound of the formulae and acid addition and quaternary ammonium salts thereof, wherein R represents a lower alkyl, particularly those having 1 to carbons such as methyl, ethyl and propyl, R represents hydrogen or a lower alkyl parand ticularly those having 1 to 5 carbons such as methyl, ethyl and propyl, and R represents a benzoyl group of the formula to an animal induces antiarrhythmic activity in the animal.

Although there is variation in amount of activity between compounds, some of the compounds provided herewith elevate, while some lower, blood pressure in animals. In addition, the compounds generally increase arterial blood flow in animals following intra-arterial injection except for S-hydroxy 2 ethylisoquinolinium halide (bromide) which decreases arterial blood flow. Increased blood flow would appear desirable in the treatment of peripheral vascular and cerebrovascular insufficiency.

The following data summarizes animal tests with compounds of this invention:

(A) 5-hydroxy-2-ethylisoquinolinium bromide (M-2) In mice it has an acute approximate LD of 63-125 mg./kg./i.p.

Following intravenous administration of 5 mg./kg. of M-2 to the bilateral vagotomized anesthetized dog, M-2 produced an increase (50-417 mm. Hg) in arterial blood pressure accompanied by a moderate increase in heart rate while essentially no effects were noted on respiratory rate.

M-2 produced slight inhibition of the carotid occlusion pressor response.

Intra-arterial administration of M-2 decreased peripheral blood flow in the anesthetized dog. s

6 M-2 was devoid of antiarrhythmic activity in the mouse (chloroform-induced ventricular fibrillation) assay procedure. However, the antiarrhythmic activity of quinidine, a well-known antiarrhythmic agent, was found to be potentiated by M-2 in this test. This is shown by the following data:

No. mice protected] No. mice dosed Dose, mg./kg./1.p.

115 EDsn 72 (64-81) Compound Q.S. M-2 plus Q.S

1 Q.S. is quinidine sulfate.

The data show that the ED for quinidine is about 48 when used with M2. This is much lower than the ED value of 72 obtained when quinidine was used alone.

(B) 5-hydroxy-2-ethyl-1,2,3,4-tetrahydroisoquinoline HBr (M-3) istration, were comparable to papaverine when each was administered intra-arterially to the anesthetized dog as shown by the following data:

Blood pressure (mm. H

Blood flow (co/min.)

B efore After B eiore After Papaverine (C) 5-(3,4,S-trimethoxybenzoyloxy)-2-ethy1-1,2,3,4- tetrahydroisoquinoline HBr (M-6) 7 rate. Intra-arterial administration of M-6 incresaed peripheral blood flow in the anesthetized dog.

(D) 5-hydroxy-2-ethyldecahydroisoquinoline hydrobromide (M-7) A dose of 10 mg./kg. administered by the intravenous route to the bilateral vagotomized anesthetized dog produced a slight rise (8 to 11 mm. Hg) in arterial blood pressure. Intra-arterial administration of M-7 produced an increase in peripheral blood flow in the anesthetized dog.

(E) 5-(4-bromobenzoyloxy)-2-ethyl-1,2,3,4,-

tetrahydroisoquinoline HCl It was studied in the dog. At doses of 5 mg./kg. intra- .venously, it produced increases in mean arterial blood 8 three experiments at a dose of mg./ kg. but was decreased ministered intravenously over a two minute period while in the experiment in response to the mg./kg. dose. recording the electro-cardiogram and femoral arterial In the mouse, it had an LD of 500 to 1,000 mg./ kg. blood pressure. In addition, each animal was observed for gross symptoms of toxicity both during and subsequent to administration of the compounds. Measurements of the electrocardiogram and blood pressure were taken during (F) 5-(2-bromobenzoyloxy)-2-ethyl-1,2,3,4- tetrahydroisoquinoline HCl i at dose of 250 mgJkgadministerefi intra' time of drug administration and at 1, 5, 10, 20, 30 and P y, 1t protecled five 9 P mlce agalnst 'E 40 minutes thereafter. Comparative drug effects were obdevelopment of ventricular fibrillation when the mice mined by calculating the mean and Standard error f were afposed su bsequenfly to chloroform' 10 change in ventricular rate, ectopic rate and blood pres- It raised arterial blood pressure 25 to 75 mm. of mercu- Sure It is to be noted that there was no significant ry at a 10 mg./kg. dosage administered intravenously to g but the pressor response a of short duration. ference (P 0.05) between the mean control values for each group prior to drug administration. Results of cal- (G) 5-(3,4,5-trimethoxybenzoyloxyl)-2-ethyldecahydroculations showed that both compounds slowed ventricular isoquinoline hydrobromide (M-8) rate and decreased ectopic ventricular rate and that there was no significant difference between the effects of the A dose of 1 to 5 mg./kg. administered by the intra two compounds. It was further noted that peak act1v1ty venous route to the bilateral vagotomized anesthetized dog d d a li h to moderate 10 to 37 mm Hg) time and duration of activity of M-8, wtihin the limits crease in arterial blood pressure. Intra-arterial administra- 0f the eXpefimental P o Compared favorably with that tion of M-S produced an increase in peripheral blood of quinidine. These data are given in the following Tables flow in the anesthetized dog. I and II.

TABLE I.EFFECT OF QUINIDINE SULFATE AND M-S ON TOTAL VENTIOULAR RATE IN CORONARY DOG FOLLOWING INTRAVENOUS ADMINISTRATION Total ventricular rate (minutes) Dose Compound mgJkg'. Control 1 min. 5 min. 10 min. 20 min. min. min.

Quinidine sulfate. 10 182=l=17 154116 152:1;14 159=e15 156:1:17 1545:14 154:1:15 M-8 2 170=l=9 161:1:7 159=l=7 150:1:8 162:1:5 162=|=6 165;|;6

1! Mean 5; standard error.

TABLE II EFFECT OF QUINIDINE SULFATE AND M-S ON VENTRICULAR ECTOPIC RATE IN CORONARY DOG FOLLOWING INTRAVENOUS ADMINISTRATION Ventricular ectopic rate (minutes) Dose mg. Compound kg./ i.v. Control 1 min. 5 min. 10 min. 20 min. 30 min. 40 min.

Quinidine sulfate 10 1695:21 925:31 905133 112:1:30 102:5:36 102:1:33 120:1:24 M-s 2 1535:14 345119 9:35:25 863:2!) 118:1:19 115;};25 128117 Compound M-8 has been found to possess antiarrhythmic activity. This indicates potential usefulness in 4.0 The comparative effect of the two compounds on blood the treatment and/or prophylaxis of cardiac arrhythmias. pressure are given in the following Table III where it Quinidine has been used successfully in the treatment of may be noted that near comparable changes were procertain types of abnormal rhythm of the human heart for duced in each group at one minute after closing, at which many years and was therefore used as the standard of time the blood pressure was elevated subsequent to M-8 comparison. M-8 compares favorably with quinidine. administration and was lowered subsequent to quinidine Although M-8 is more potent, it is also more toxic and as administration. It should further be noted that qualitative a result the two compounds appear to possess a near comsigns of gross toxicity were essentially comparable in each parable safety factor. The term, safety factor, is the group while quantitative differences in toxic symptoms ratio of the toxic dose to the effective dose. were not readily apparent.

TABLE III.-EFFECT OF QUINIDINE SULFATE AND M-8 ON ARTERIAL BLOOD PRESSURE IN CORONARY DOG FOLLOWING INTRAVENOUS ADMINISTRATION Mean blood pressure (mm. Hg.)

Dose, mg./

Compound kg./i.v. Control 1min. 5min. 10min. 20 min. 30min. 40 min.

Quinidine sulfate 10 76:1:5 64=l:8 735:8 665:7 72i8 66:1;8 665:9 M-s 2 89:};5 9&4 865:6 895:6 855:5 84:1:5 845:4

M-8 and quinidine were studied for antiarrhythmic The oral absorption of quinidine sulfate and M8 was activity in dogs with ventricular arrhythmia produced eX- studied in eight additional dogs which were similarly perimentally by interrupting blood flow to the myocardiprepared by surgical treatment. Three animals served as um. In this test, animals are prepared by opening the controls and received 5 ml./kg. of 0.9% NaCl, two thorax and ligating the anterior descending branch of received 20 mg./ kg. of quinidine sulfate and the remainthe left coronary artery. Test compounds are then evaluing three received 8 mg./kg. of M-8. The compounds ated for antiarrhythmic activity on the first postoperative were dissolved in 0.9% NaCl and administered with the day when the animal is in the unanesthetized state. aid of a stomach tube. Electrocardiogram measurements Two groups f dogs consisting f 6 animals Per group were recorded (Table IV) and each dog was observed for were surgically prepared as described. Group I received g of gross tOXlcitY- Overt tOXic slgns Were not observed 10 mg./ kg. of quinidine sulfate and Group II received in these animals and the effect of the different treatments 2 mg./kg. of compound M8. Each compound was adon ectopic rate is given in the following Table V.

TABLE IV Total ventricular rate (minutes) Dose, mg./

Compound kg./oral Control 1 hour 2hours 3hours 4hours fihours 0.9% NaCl 207 198 204 195 Quinidine sulfa 20 186 178 148 166 148 152 1-8 8 163 136 122 122 131 when warranted.

TABLE V Ventricular ectopic rate (minutes) Dose, mg./

Compound kg./oral Control 1 hour 2 hours 3 hours 4 hours 5 hours 0.9% NaCl n95 190 199 181 Quinidine sulfate 20 152 156 58 146 100 113 M-8 s 143 i 97 67 45 72 68 Comparative toxicity studies using quidine sulfate and EXAMPLE 2 M-8 were conducted 1n twelve add1t1ona1nnanesthet1zed 5 hydroXy 2 ethy1 1,2,34 tetrahydroisoquinoline dogs which had not previously rece ved any form of treathydmbromide ment. Six dogs received 20 mg./l g. of quinidine'sulfate and six received 4 mg./kg. of M-S. At these dose levels,

no difference between the compounds was readily apparent in either the nature or severity of toxic signs.

The J. Med. Chem. 11, 997 (1968) also reports the antiarrhythmic activity for 5-(3,4,5-trimethoxybenzoyloxy)-2-ethyldecahydroisoquinoline (M-8) and 5-(3,4,5- trimethoxybenzoyloxy) 2 methyldecahydroisoquinoline and shows both are more potent than quinidine.

The active agents of this invention can be administered to animals as pure compounds. It is advisable, however, to first combine one or more of the compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid can be used. Solid carriers such as starch, sugar, talc and the like can be used to form powders. The powders can be used for direct administration or they may be used to make tablets or fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as acacia and gelatin, and disintegrating agents like sodium carbonate in combination with citric acid, or methylcellulose or starch separately, can be used to form tablets.

Unit dosage forms such as tablets and capsules can contain any suitable predetermined amount of one or more of the active agents, and may be administered one or more at a time at regular intervals. Such unit dosage comsitions can contain, for example, from about 0.02 to 500 mg. of active agent. However, about mg. is considered the highest amount which is needed for the active compounds in the unit dosages. Such unit dosage forms, however, should generally contain a concentration of 0.1% to 50% by weight of one or more of the active compounds.

The oral route of administration is preferred. However, other routes, such as by' injection, can be employed The following examples are presented to illustrate the preparation of compounds within the scope of this invention.

EXAMPLE 1 S-hydroxy-2-ethylisoquinolinium bromide Forty grams (0.28 mole) of S-hydroXyisoquinoline was dissolved in 100 ml. of absolute ethanol and refluxed for 8 hours on a steam bath with 50% excess ethyl bromide (40 g.) (0.37 mole). The ethanol and excess ethyl bromide was then evaporated off and the resulting brown solid recrystallized from ethanol to yield 57.47 g. (82%) of light brown needles, M.P. 209.4-210.6 C.

Analysis.Calcd. for C H N0Br (percent): C, 51.97;

H, 4.73; N, 5.51; Br, 31.50. Found (percent): C, 51.77;

H, 4.68; N, 5.13; Br, 31.50. i

Five grams (0.0196 mole) of 5-hydroxy-2-ethylisoquinolinium bromide was dissolved in 250 ml. of absolute ethanol and hydrogenated (Parr hydrogenation apparatus) over 300 mg. of Adams platinum oxide at 40 lbs. per sq. in. pressure at room temperature. A white crystalline solid separated when the hydrogenation was terminated (5 hrs.). The hydrogenated suspension was heated on a steam bath until the precipitated solid had redissolved; the exhausted catalyst was then filtered oil. The filtrate was concentrated, from which 4.5 g. of colorless plates crystallized on cooling, M.P. 223.8224.6 C. The ultraviolet spectrum of this compound had A 272. and 277 m (log 53.24 and 3.23, respectively).

Analysis.Calcd. for C H NOBr (percent): C, 51.17; H, 6.20; N, 5.43; Br, 31.01. Found (percent): C, 51.17; H, 6.06; N, 5.42; Br, 31.28.

EXAMPLE 3 5-(3,4,S-trimethoxybenzoyloxy) -2-ethyl-1,2,3,4- tetrahydroisoquinoline hydrobromide Four and three-tenths grams (0.0166 mole) of S-hydroxy 2 ethyl 1,2,3,4-tetrahydroisoquinoline hydrobromide was dissolved in ml. of water and sodium hydroxide solution added until no further precipitation was evident. The resulting suspension was extracted with ether, dried, and the solvent removed to yield 3.0 g. (100%) of white solid. This base was dissolved in 100 ml. of dry benzene and added to a solution of 4.0 g. (0.0173 mole) of 3,4,5-trimethoxybenzoyl chloride in 100 ml. of dry benzene. Two grams of dry sodium bicarbonate was added to this mixture and the whole refluxed for 8 hours on a steam bath. The gelatinous precipitate which separated out was filtered (3.3 g.) and the filtrate extracted with dilute hydrochloric acid. This acid extract, made alkaline with sodium hydroxide, was extracted with ether and dried. The ether was removed to yield 3.6 g. of a pale yellow oil. The hydrobromide salt of this base was recrystallized from ethanol-ether to yield 3.7 g. (32.3%) as short white needles, M.P. 213.2-213.4 C.

Analysis.-Calcd. for C H NO Br (percent): C, 55.75; H, 5.75; N, 3.10; Br, 17.70. Found (percent): C, 55.59; H, 5.71; N, 3.18; Br, 17.80.

l-EXAMPLE 4 S-hydroxydecahydroisoquinoline and hydrochloride Five grams of S-hydroxyisoquinoline was dissolved in 50 ml. of glacial acetic acid and 0.5 ml. of concentrated sulfuric acid added. The resulting solution was hydrogenated over 5 g. of Adams platinum oxide at 50 lbs. per sq. in. pressure for 36 hours at room temperature. The exhausted catalyst was filtered from the hydrogenated solution and the filtrate diluted with approximately 50 ml. of water, made alkaline by the addition of sodium hy- "droxide pellets, and extracted with ether. The dried ethereal extract was evaporated carefully to yield a yellow oily residue (2.7 g.) which was treated with dry hydrogen chloride in ether to yield 2.9 g. (51%) of the base hydrochloride, recrystallized from ethanol-ether, M.P. 19'1.0-193.0 C. Theultraviolet spectrum of this compound was taken in water and showed no absorption throughout the range 220-340 mp.

H, 9.38; N, 7.29; Cl, 18.75. Found (percent) :C, 56.33; H,-

9.43; N, 7.22; CI, 18.80.

EXAMPLE v S-hydroxy-2-ethyldecahydroisoquinoline and hydrobromide Eight grams (0.031 mole) of 5-hydroxy-2-ethylisoquinolinium bromide was treated with moist silver oxide, prepared from the action of sodium hydroxide on silver nitrate (13 g.) in 100 ml. of a 50% aqueous methanol solution for 24 hours. The silver bromide formed was then filtered from the solution using celite/charcoal rnix ture as a filter aid. The solvent was evaporated off under reduced pressure at as low a temperature as possible to yield 5.7 g. (96%) of 5-hydroxy-2-ethylisoquinolinium hydroxide. This compound was hydrogenated as described in Example 4. The resulting 5-hydroxy-2-ethyldecahydroisoquinoline was converted to the hydrobromide 5.62 g. (81%), which was recrystallized from ethanol-ether to yield fine white needles, M.P. 218.4219.0 C. The ultraviolet spectrum of this compound indicated no absorption in the range 220-310 m Analysis.Calcd. for 'C H NOBr (percent): C, 50.00; H, 8.33; N, 5.30; Br, 30.31. Found (percent): C, 49.80; H, 8.31; N, 5.52; Br, 30.38.

EXAMPLE 6 5- 3,4,5-trimethoxybenzoyloxy) -2-ethyldecahydroisoquinoline and hydrobromide Five grams (0.027 mole) of 5-hydroxy-2-ethyldecahydroisoquinoline was dissolved in 20 ml. of sodium dried toluene and added to a solution of 15 g. (0.065 mole) of 3,4,5 trimethoxybenzoyl chloride and refluxed for 48 hours. The resulting suspension was filtered and the toluene filtrate extracted with dilute hydrochloric acid. Neutralization of this acid extract was followed by extraction with ether. The ether extract was dried and evaporated to yield a brown viscous oil. This was purified by chromatography on an activated magnesium silicate column and eluted with petroleum ether (GO-90 C.)-ether (:1). Large prisms separated from the fractions on standing overnight. This material was crystallized from petroleum ether (30-60 C.) to yield 4.52 g. (52%) of large prisms, M.P. 99.8- 100.3 C.

Analysis.-Ca1cd. for C H NO (percent): C, 66.82; H, 8.28; N, 3.71. Found (percent): C, 67.06; H, 8.32; N, 3.64.

One gram of the base was converted to the hydrobromide and recrystallized from ethanol-ether to yield 1.06 g. (88%) of short white needles, M.P. 197.8-1986" C Analysis.-Calcd. for C H NOgBr (percent): C, 55.02; H, 7.04; N, 3.06; Br, 17.43. Found (percent): C, 55.12; H, 7.15; N, 3.11; Br, 17.50.

EXAMPLE 7 5 (4-bromob enzoyloxy -2-ethyl-1,2,3 ,4-tetrahydroisoquiuoline hydrochloride 1 S-hydroxy 2 ethyl-1,2,3,4-tetrahydroisoquinoline (4.0 g.) was dissolved inanhydrous toluene, 0.5 g. of anhydrous potassium carbonate was added and then 7 g. of 4-bromobenzoyl chloride. The mixture was refluxed for a period of 16 hours. The reaction mixture was filtered and the toluene filtrate treated with dilute hydrochloric acid. The precipitated solid (2.4 g.) was filtered and recrystallized from ethanol; M.P. 239.5-240.5 C.

Analysis.-Calcd. for C H NO Brcl (percent): C, 54.50; H, 4.83; N, 3.53; Br, 20.14; Cl, 8.94.

Found (percent): C, 54.34; H, 4.61; N, 3.70; Br, 20.39; Cl, 8.80.

Additional product was obtained from the acid aqueous extract.

EXAMPLE 8 'sabiomobenzeylux 26mm,zrmaraliydre isoquinoline hydrochloride 5=hydroxy 2 -'ethy1-1,2,3,4-tetrahydroisoquinoline *-(2.7

g.) was dissolved in 200 ml. of dry toluene, 0.5 g. of

-aahydrouslpgtass m carbona e W s a de and t e m ture refluxed with 7 g. of 2-bromobenzoyl chloride for 18 hours. The reaction mixture was filtered and the toluene filtrate extracted with dilute hydrochloric acid. The aqueous acid extract was evaporated to dryness to yield 4.0 g. of sticky solid which was recrystallized from ethanol-ether; M.P. 210-211 C.

Analysis.-Calcd. for C H NO BrCl (percent): C, 54.50; H, 4.83; N, 3.53; Br, 20.14; Cl, 8.94.

Found (percent): C, 54.66; H, 5.02; N, 3.63; Br, 9.0-6; Cl, 20.28. EXAMPLE 9 Cis and trans-5,9,10-H-5-(3,4,5-trimethoxybeuzoy1- oxy) -2-methyldecahydroisoquinoline Cis-5,9,10-H-5-hydroxy- 2 methyldecahydroisoquinoline (1.01 g.) prepared as disclosed in Mathison and Gueldner, J. Org. Chem, 33, 2510 (1968) was dissolved in ml. of dry pyridine and treated with excess 3,4,5- trirnethoxybenzoyl chloride for 4 days at room temperature. The pyridine was removed in vacuo and the tacky residue was made alkaline with potassium carbonate solution and extracted with ethyl ether. Evaporation of the dried ethyl ether extract yield 1.86 g. of a viscous oil which was recrystallized from benzene-pentane to yield 0.5 g. of needles; M.P. 91.8-93 C. for cis-5,9',10-H-5- (3,4,5 trimethoxybenzoyloxy) 2 methyldecahydroisoquinoline.

In a similar manner, trans-9,10-t-5-H-5-(3,4,5-trimethoxybenzoyloxy 2 methyldecahydroisoquinoline, M.P. 103-104 C., was produced by reacting 3,4,5-trimethoxy- 'benzoyl chloride with trans-9,10-t-5-H-5-hydroxy-2-methyldecahydroisoquinoline as produced according to Mathison and Gueldner, J. Org. Chem. 33, 2510 (1968).

EXAMPLE 10 Cis-5,9,10-H-5-(3,4,S-trimethoxybenzoyloxy) -2- ethyldecahydroisoquinoline Cis-5,9,10-H-5-hydroxy 2 ethyldecahydroisoquinoline (0.085 g.) prepared as disclosed in Mathison et al., J. Med. Chem. 11, 997 (1968) was reacted with 0.1 g. of 3,4,5-trimethoxybenzoyl chloride according to Mathison,

J. Org. Chem. 30, 3558(1965) to give 0.07 g. of product.

13 14 wherein R is lower alkoxy and R is lower alkyl and non 3,379,730 4/1968 Mathison 260286 toxic acid addition salts and lower alkyl quaternary there- 3,475,538 10/1969 Mathison 42 1--25 8 of.

References Cited DONALD G. DAUS, Primary Examiner UNITED STATES PATENTS 5 Us. CL 2,800,475 7/1957 Robinson 260287 3,317,541 2/1967 Omezawa 260287 260 239'1286289;424258 Patent No. 3,583,994 Dated June 8, 1971.

Inventor(s) lav William Mathison It: is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col 3 line 3, "l-lower" should be 2- l ewerline 51 "p eparation" should be --preparation Col 1 llne 55 "ll-R" in the formula should be -N-R Col 8 Table "150*:8" should be l601-8 Table l "131" should l??? l2i e Col 9 1 inc 41 "comsitiofis" should be -cempositi0ns Col 13, line 2 after "quaternurf' insert ammonium sa1ts-.

Signed and sealed thi S 26th day 0F October l 971 (SEAL) Attest:

EDWARD M. FLETCHER,JR.

ROBERT GOTTSCHALK Attesting Officer Acting'Commissioner of Patents 

